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A large number of barbiturates have been introduced into clinical medicine, but only 2 remain in use as intravenous anesthetics: thiopental (a thiobarbiturate) and methohexital (an oxybarbiturate; Fig. 41-1 and Table 41-1). Both of these medications are practically insoluble in water; however, they are weak acids, and their sodium salts are freely soluble in water. Thiopental is no longer available in the United States.
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The usual concentrations of the sodium salts used clinically are 2.5% thiopental and 1% methohexital. Thiopental is soluble at higher concentrations, but pain on injection is likely to occur. The 2.5% thiopental solution usually is painless when given intravenously. This solution is irritating to tissues if it extravasates because it has a pH between 10 and 11. If accidentally injected intra-arterially, vasospasm and thrombosis may occur that can lead to limb loss if not treated rapidly. Recommended treatments include intra-arterial injection of a vasodilator (eg, papaverine or nitroglycerin) and an anticoagulant (eg, heparin). The 1% methohexital solution is more likely to cause pain after intravenous injection; however, it is well tolerated after intramuscular injection and can be given via this route in a patient who does not have intravenous access. Methohexital is also hazardous if inadvertently injected intra-arterially.
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Both thiopental and methohexital are supplied in powdered form and usually are reconstituted with sterile, preservative-free water (although normal saline can be used). Neither reconstituted solution is stable in the long term, and the manufacturer's package inserts state that they are stable at room temperature for 24 hours. Despite this conservative recommendation, thiopental has been shown to be both chemically stable and bacteriologically sterile for at least 1 week after reconstitution when refrigerated.37 Under refrigeration, methohexital remains chemically stable and microbiologically sterile for at least 6 weeks.38
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Central Nervous System
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Like propofol, thiopental has its primary neuronal action at the γ-aminobutyric acid (GABA)A receptor. Although barbiturates allosterically affect GABA binding (and vice versa), GABA is not necessary for barbiturate action on the channel.39
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The barbiturates are classified as sedative–hypnotics; they produce dose-related depression of the CNS, ranging from mild sedation to unconsciousness. Thiopental or methohexital rapidly produces unconsciousness, and awakening will occur in minutes unless additional drugs are given. When administered in subhypnotic doses, barbiturates can sometimes produce disinhibition and "paradoxical" excitation. These drugs are not analgesics, and suppression of movement or hemodynamic responses to painful stimuli requires plasma concentrations in excess of those needed to cause unconsciousness. Like propofol, thiopental decreases ICP, CBF, and CMRo2. In some instances thiopental may exert a "neuroprotective" effect (see later) in which decreased oxygen delivery to the CNS (eg, during clamping of an intracranial artery) may be less likely to result in CNS damage because there has been a profound drug-induced decrease in oxygen utilization.
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Because of its effects on CMRo2, CBF, and ICP, intravenous thiopental injection may produce beneficial effects in patients with intracranial space-occupying lesions or cerebral edema associated with a brain tumor, intracranial hemorrhage, or head trauma (Table 41-2). The effect of thiopental on CPP in the supine patient is unpredictable. Thiopental decreases mean arterial pressure in a dose-dependent manner (see Cardiovascular System); however, if CPP is low in a patient because of an elevated ICP, the overall effect of thiopental may be beneficial.40
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The ability of thiopental to produce "neuroprotection" is both variable and controversial. When thiopental is given in advance of a planned reduction or interruption of cerebral perfusion, the likelihood or severity of subsequent CNS damage appears to be less.41 In contrast, when thiopental is given after the onset of cerebral ischemia, such as following a cardiac arrest, no apparent beneficial effect is seen.42 Protective efficacy appears to be superior when the size of the ischemic area is smaller and when the total duration of ischemia is shorter (see Chapter 85 for detailed considerations on this topic).
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Thiopental produces a dose-dependent effect on the EEG (Fig. 41-3).43 At sedative doses or at doses associated with excitation or disinhibition ("stage 2" anesthesia), median EEG frequency increases because alpha waves (7-13 Hz) typical of the awake state change to beta waves (13-30 Hz). As the depth of hypnosis increases, there is a decrease in frequency and an increase in amplitude (power) of the EEG waves. Surgical anesthesia is associated with an EEG characterized by a predominance of delta waves (0.5-3.5 Hz). Increasing the dose of thiopental further leads to burst suppression (characterized by alternating periods of delta waves and electrical inactivity) and, finally, a completely isoelectric ("flat-line") EEG. An isoelectric or burst suppression EEG pattern is associated with a profound decrease in both CMRo2 and CBF, and this end point has been used to titrate the dose of thiopental for brain protection studies. Some studies suggest that alternative mechanisms (eg, decrease in amino acid–induced excitotoxicity) are more important than reducing cerebral metabolic rate.44
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Thiopental is an excellent anticonvulsant. The typical intravenous anesthetic induction dose of 4 to 7 mg/kg usually is effective in rapidly terminating seizures. Refractory status epilepticus is often treated with repeated boluses or with continuous infusion of thiopental; such patients usually also require mechanical ventilatory support and may require infusion of vasopressors (see Cardiovascular System).
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In contrast to thiopental, methohexital may cause abnormal spiking activity of the EEG and may elicit seizures in patients with a seizure disorder, especially in those with psychomotor epilepsy. For this reason, methohexital has long been used as the hypnotic agent to render patients unconscious for electroconvulsive therapy. Methohexital is also associated with abnormal motor activity during induction of general anesthesia, such as myoclonic jerks, muscle tremors, and hiccoughs.
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The respiratory effects of thiopental are very similar to those of propofol (Table 41-3). At the usual intravenous anesthetic induction dose of 4 to 7 mg/kg, most patients will become apneic for a few minutes. Accompanying this ventilatory depression is a decrease in protective airway reflexes, although overall responsiveness of the airway is increased. The incidence of coughing and laryngospasm during induction is higher with barbiturates than with most other sedative–hypnotics.
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Thiopental produces an increase in the circulating concentration of histamine (see Hypersensitivity Reactions). The effect of histamine on the respiratory musculature is to cause constriction in the trachea and dilation in smaller airways. Typically no net alteration in bronchial resistance occurs.45
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Cardiovascular System
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Thiopental typically causes a transient, although significant, decrease in systemic blood pressure when it is administered to induce general anesthesia (Table 41-4).46 This decrease in blood pressure is exaggerated in persons with preexisting cardiac dysfunction or hypovolemia, those given opioid or benzodiazepine premedication, or those receiving therapy with β-adrenergic blockers or vasodilators. Thiopental-induced hypotension is more pronounced in older patients and when the drug is administered rapidly. Thiopental has a direct effect on the heart, decreasing contractility and leading to a decrease in cardiac output. It also has a direct effect on both systemic arteries and veins, causing vasodilatation. This vasodilatation results in decreased systemic arterial pressure as well as decreased venous return to the heart, the latter effect compounding the decrease in cardiac output and blood pressure. An equipotent dose of methohexital causes slightly less hypotensive effect than does thiopental. Thiopental increases the pulmonary vascular resistance in rat lung,47 although this effect may not be significant in humans.48
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Hypersensitivity Reactions
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In an anaphylactic reaction, there is IgE-mediated release of vasoactive and immune mediators from mast cells and basophils. An anaphylactoid reaction results when a drug directly causes the release of some of these mediators from mast cells or basophils. Anaphylaxis and other true immunologic reactions to barbiturates are extremely rare. They occasionally produce an anaphylactoid reaction by displacing vasoactive mediators from tissue mast cells or basophils. Thiopental injection increases the circulating concentration of histamine 3.5-fold, with the histamine concentration returning to baseline within 10 minutes.49 This effect contributes to the overall decrease in systemic vascular resistance produced by the drug. Anaphylactic or anaphylactoid reactions to thiopental are much less common than are perioperative reactions to latex exposure or injection of muscle relaxants and antibiotics.50
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Barbiturates are the prototypical inducers of the hepatic microsomal enzyme system, including the cytochromes P450 (CYP) and the glucuronyl transferases. The rate of metabolism of some medications may be increased in the postoperative period if a patient is given thiopental for anesthesia induction, although this effect is rarely of clinical consequence. Thiopental is also an inducer of the enzyme δ-aminolevulinic acid (ALA) synthase, an enzyme that catalyzes the initial step in the biosynthesis of heme. Thiopental is absolutely contraindicated in persons with certain porphyrias (Fig. 41-4). In 3 of the clinically important porphyrias, there is a deficiency in a heme biosynthetic enzyme that follows ALA synthase in the pathway, and ALA, which is neurotoxic, then accumulates. These 3 porphyrias are acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria,51 and the enzyme deficiencies responsible for them are shown in Fig. 41-4. Each of these is transmitted as an autosomal-dominant trait, so affected individuals usually are heterozygotes with approximately half the normal amount of enzyme. Interestingly, a fourth variety, porphyria cutanea tarda, also due to a deficiency in a heme biosynthetic enzyme, is not a contraindication to use of a barbiturate.51 Anesthetic medications generally considered safe or unsafe in persons with porphyria are listed in Box 41-2.
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Thiopental decreases renal blood flow and increases the secretion of antidiuretic hormone. The actions act together to decrease urine output.
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In comparison with propofol (see Propofol, Nausea and Vomiting), thiopental used for anesthesia induction results in a higher incidence of postoperative nausea and vomiting. In sedative (ie, subhypnotic) doses, thiopental causes hyperalgesia (ie, it decreases the threshold to pain).52 This effect (and thiopental's tendency to accumulate) makes it a poor choice for intraoperative sedation during regional anesthesia or monitored anesthesia care. Thiopental is safe to use in patients susceptible to malignant hyperthermia.
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Thiopental is administered as the alkaline (pH 10-11) solution of its sodium salt, but it is buffered to physiologic pH immediately upon contacting the circulation. Because its pKa is 7.5, at physiologic pH slightly more than 50% of the thiopental molecules are uncharged and therefore lipid soluble. Its oil/water partition coefficient of approximately 500 is more than twice that of halothane, indicating that it is highly lipid soluble. This high lipid solubility, coupled with the large fraction of the cardiac output typically delivered to the brain, is responsible for the very rapid onset of effect, typically well under 1 minute, after intravenous administration.
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Thiopental is approximately 85% bound to plasma protein. Protein-bound thiopental is unable to diffuse across the blood–brain barrier and produce a pharmacologic effect. In addition, the extensive binding of thiopental limits overall hepatic clearance, as only free drug is taken up by the liver to be metabolized. In clinical situations in which the plasma concentration of protein is decreased (eg, hepatic disease or hemodilution due to fluid resuscitation), the free fraction of thiopental is elevated, and lower doses of thiopental may be needed.
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Thiopental has a redistribution half-life (t½α) of approximately 2 to 4 min,53 indicating that, after a typical bolus injection, the effect of the drug will be terminated within 3 to 4 half-lives or approximately 6 to 16 minutes (Table 41-5). Redistribution out of the CNS is the primary process by which the pharmacologic effects of thiopental are terminated. Unless the drug is given in very large doses (eg, barbiturate coma), in repeated doses, or by a long continuous infusion, metabolism and elimination are much less important in terminating its effect.
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Metabolism and Elimination
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Thiopental has a terminal half-life (t1/2β) of approximately 6 to 12 hours.53 Thiopental undergoes an interesting metabolic reaction catalyzed by CYP. The initial step is oxidation of the sulfur atom, forming a sulfoxide derivative that spontaneously rearranges, leaving oxygen in place of the sulfur in the barbiturate ring. This metabolite is the active barbiturate, pentobarbital. Because of slower redistribution, pentobarbital is a longer-acting drug than thiopental. Thus, when large cumulative doses of thiopental are given, clinically significant concentrations of pentobarbital occur. Pentobarbital contributes to the overall effect and makes thiopental appear as a much longer-acting medication.54 Other inactive hydroxylated metabolites of thiopental also are produced. Methohexital has a lower volume of distribution and a higher hepatic clearance than thiopental, and it is metabolized to inactive hydroxylated metabolites (Table 41-5).
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Factors Affecting Pharmacodynamics and Pharmacokinetics
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Many factors affect the pharmacodynamics and pharmacokinetics of thiopental. For example, elderly patients require lower doses of thiopental to produce unconsciousness. This altered response is due to the decreased rate of distribution from the central compartment to the rapidly equilibrating compartment.55
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The pharmacokinetics of thiopental in persons with significant impairment of hepatic function is complex. The fraction of unbound thiopental is increased because of decreased plasma albumin concentrations, but hepatic clearance of unbound drug is decreased. Total clearance remains normal.53 Persons with cardiac dysfunction typically have an exaggerated hypotensive response to thiopental. In patients who are hypovolemic, a lower thiopental dose is needed because a greater fraction of the cardiac output goes to the brain. The hypovolemic patient may tolerate thiopental-induced vasodilatation very poorly.
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Induction of Anesthesia
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The characteristics of thiopental as an induction agent are listed in Table 41-7. An induction dose of 4 to 7 mg/kg is reasonable in the typical healthy patient undergoing elective surgery. Coexisting factors, such as previous premedication (eg, with benzodiazepines and/or opioids), advanced age, or presence of concurrent disease (eg, cardiac dysfunction, COPD, hypovolemia) will decrease the required dose of thiopental. Patients with acquired tolerance because of chronic use of barbiturates or cross-tolerance to benzodiazepines, anticonvulsants, or alcohol may require higher doses of thiopental to produce unconsciousness.
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If there is concern about a possibly exaggerated response to thiopental, a prudent practice would be to administer the induction dose slowly or in divided doses, using a small initial bolus as a "test dose" and waiting 1 to 2 minutes to evaluate the central nervous and hemodynamic responses.
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After administration of the induction dose, consciousness typically is lost within 30 seconds, although this time may be longer in persons with a slow circulation time because of cardiac dysfunction. Recovery of consciousness usually occurs within 6 to 16 minutes; however, some degree of cognitive impairment (a "hangover") may persist for hours.
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The induction dose of methohexital is 1 to 3 mg/kg. Onset and awakening are similar to those with thiopental; however, the duration of cognitive impairment will be somewhat shorter. As mentioned previously, excitatory effects like twitching and hiccoughs are often seen during induction.
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Maintenance of Anesthesia
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General anesthesia can be maintained by either intermittent intravenous boluses or a continuous intravenous infusion of thiopental; however, a rapid recovery should not be anticipated. Giving any rapidly redistributed medication by intermittent bolus results in a series of peaks and troughs in both blood concentration and effect, typically causing alternating periods of overmedication and undermedication. A continuous infusion, typically following a loading dose, permits a more constant blood (and brain) concentration and effect (see Chapter 43).
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The CSHTs for thiopental after 1- and 2-hour infusions are approximately 80 and 100 minutes, respectively (Fig. 41-2). Thus thiopental is not a good choice for a maintenance infusion when rapid emergence and recovery are desired.
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Methohexital has shorter CSHT values than does thiopental. The CSHTs for methohexital after 1- and 2-hour infusions are approximately 26 and 48 minutes, respectively (Fig. 41-2). Although shorter than for thiopental, emergence and recovery after an infusion of methohexital are still prolonged.
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Barbiturates are infrequently used for procedural sedation (except perhaps the use of methohexital during office-based oral surgical procedures). In subhypnotic doses, thiopental is less likely than propofol to produce anterograde amnesia9 (usually considered a desirable effect), and there may be hyperalgesia to pain.